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DOI 10.1126/scitranslmed.aad5169

Медицинская библиотека · Science translational medicine · 2016

Quantifying prion disease penetrance using large population control cohorts.

Minikel Eric Vallabh, Vallabh Sonia M, Lek Monkol, Estrada Karol, Samocha Kaitlin E, Sathirapongsasuti J Fah, McLean Cory Y, Tung Joyce Y, Yu Linda P C, Gambetti Pierluigi, Blevins Janis, Zhang Shulin, Cohen Yvonne, Chen Wei, Yamada Masahito, Hamaguchi Tsuyoshi, Sanjo Nobuo, Mizusawa Hidehiro, Nakamura Yosikazu, Kitamoto Tetsuyuki, Collins Steven J, Boyd Alison, Will Robert G, Knight Richard, Ponto Claudia, Zerr Inga, Kraus Theo F J, Eigenbrod Sabina, Giese Armin, Calero Miguel, de Pedro-Cuesta Jesús, Haïk Stéphane, Laplanche Jean-Louis, Bouaziz-Amar Elodie, Brandel Jean-Philippe, Capellari Sabina, Parchi Piero, Poleggi Anna, Ladogana Anna, O'Donnell-Luria Anne H, Karczewski Konrad J, Marshall Jamie L, Boehnke Michael, Laakso Markku, Mohlke Karen L, Kähler Anna, Chambert Kimberly, McCarroll Steven, Sullivan Patrick F, Hultman Christina M, Purcell Shaun M, Sklar Pamela, van der Lee Sven J, Rozemuller Annemieke, Jansen Casper, Hofman Albert, Kraaij Robert, van Rooij Jeroen G J, Ikram M Arfan, Uitterlinden André G, van Duijn Cornelia M, Exome Aggregation Consortium (ExAC), Daly Mark J, MacArthur Daniel G

СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАПоддержка правительства СШАПоддержка службы здравоохранения СШАПеревод в очереди

Аннотация

More than 100,000 genetic variants are reported to cause Mendelian disease in humans, but the penetrance-the probability that a carrier of the purported disease-causing genotype will indeed develop the disease-is generally unknown. We assess the impact of variants in the prion protein gene (PRNP) on the risk of prion disease by analyzing 16,025 prion disease cases, 60,706 population control exomes, and 531,575 individuals genotyped by 23andMe Inc. We show that missense variants in PRNP previously reported to be pathogenic are at least 30 times more common in the population than expected on the basis of genetic prion disease prevalence. Although some of this excess can be attributed to benign variants falsely assigned as pathogenic, other variants have genuine effects on disease susceptibility but confer lifetime risks ranging from <0.1 to ~100%. We also show that truncating variants in PRNP have position-dependent effects, with true loss-of-function alleles found in healthy older individuals, a finding that supports the safety of therapeutic suppression of prion protein expression.

Для цитирования: Minikel Eric Vallabh, Vallabh Sonia M, Lek Monkol, Estrada Karol, Samocha Kaitlin E, Sathirapongsasuti J Fah, McLean Cory Y, Tung Joyce Y, Yu Linda P C, Gambetti Pierluigi, Blevins Janis, Zhang Shulin, Cohen Yvonne, Chen Wei, Yamada Masahito, Hamaguchi Tsuyoshi, Sanjo Nobuo, Mizusawa Hidehiro, Nakamura Yosikazu, Kitamoto Tetsuyuki, Collins Steven J, Boyd Alison, Will Robert G, Knight Richard, Ponto Claudia, Zerr Inga, Kraus Theo F J, Eigenbrod Sabina, Giese Armin, Calero Miguel, de Pedro-Cuesta Jesús, Haïk Stéphane, Laplanche Jean-Louis, Bouaziz-Amar Elodie, Brandel Jean-Philippe, Capellari Sabina, Parchi Piero, Poleggi Anna, Ladogana Anna, O'Donnell-Luria Anne H, Karczewski Konrad J, Marshall Jamie L, Boehnke Michael, Laakso Markku, Mohlke Karen L, Kähler Anna, Chambert Kimberly, McCarroll Steven, Sullivan Patrick F, Hultman Christina M, Purcell Shaun M, Sklar Pamela, van der Lee Sven J, Rozemuller Annemieke, Jansen Casper, Hofman Albert, Kraaij Robert, van Rooij Jeroen G J, Ikram M Arfan, Uitterlinden André G, van Duijn Cornelia M, Exome Aggregation Consortium (ExAC), Daly Mark J, MacArthur Daniel G. Quantifying prion disease penetrance using large population control cohorts.. Science translational medicine. 2016. DOI: 10.1126/scitranslmed.aad5169.

Предметные рубрики MeSH

Case-Control StudiesCohort StudiesGenetic Predisposition to DiseaseHumansMutationPenetrancePrion DiseasesPrionsRisk Factors
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